Prediction of longer-term outcome of treatment-resistant depression in tertiary care.

BACKGROUND: Systematic studies on the outcome of treatment-resistant depression are scarce. AIMS: To describe the longer-term outcome and predictors of outcome in treatment-resistant depression. METHOD: Out of 150 patients approached, 118 participants with confirmed treatment-resistant depression (unipolar, n = 77; bipolar, n = 27; secondary, n = 14) treated in a specialist in-patient centre were followed-up for between 8 and 84 months (mean = 39, s.d. = 22). RESULTS: The majority of participants attained full remission (60.2%), most of whom (48.3% of total sample) showed sustained recovery (full remission for at least 6 months). A substantial minority had persistent subsyndromal depression (19.5%) or persistent depressive episode (20.3%). Diagnosis of bipolar treatment-resistant depression and poorer social support were associated with early relapse, whereas strong social support, higher educational status and milder level of treatment resistance measured with the Maudsley Staging Method were associated with achieving quicker remission. Exploratory analysis of treatment found positive associations between treatment with a monoamine oxidase inhibitor (MAOI) in unipolar treatment-resistant depression and attaining remission at discharge and at final follow-up, and duloxetine use predicted attainment of remission at final follow-up. CONCLUSIONS: Although many patients with treatment-resistant depression experience persistent symptomatology even after intensive, specialist treatment, most can achieve remission. The choice of treatment and presence of good social support may affect remission rates, whereas those with low social support and a bipolar diathesis should be considered at higher risk of early relapse. We suggest that future work to improve the long-term outcome in this disabling form of depression might focus on social interventions to improve support, and the role of neglected pharmacological interventions such as MAOIs.

Long-term impact of residual symptoms in treatment-resistant depression.

OBJECTIVE: Although commonly encountered, little work has defined the longitudinal course of treatment-resistant depression (TRD) and the influence of residual posttreatment symptoms on longer-term outcome. The aim of our study was to assess the impact of posttreatment clinical states on longer-term outcome. METHOD: Patients (n = 118) with TRD received specialist inpatient treatment and were followed-up for a median of 3 years. Longitudinal outcome dichotomized into good and poor outcome was used as the primary outcome and functional measures were used as secondary outcomes. RESULTS: Among 118 treated patients, 40 (34%) entered clinical remission, 36 (31%) entered partial remission, and 42 (37%) remained in episode at discharge. At follow-up, 35% had longitudinally defined poor outcome. Posttreatment clinical status was the main predictor of both poor and good outcome. Nearly 50% of patients achieved postdischarge recovery, and subsequently had longer-term outcome, comparable with patients discharged in remission. Patients who remained in episode posttreatment were more symptomatically and functionally impaired. CONCLUSION: Posttreatment clinical states are a useful guide to clinicians for projecting the longer-term outcome of patients with TRD. The persistence of residual or syndromal symptoms predicts a poorer longer-term outcome, whereas treatment to remission is associated with better outcomes.

An exploration of testosterone levels in patients with bipolar disorder.

BACKGROUND: Testosterone influences well-being, mood and cognition and may play a role in the pathophysiology of bipolar disorder. AIM: To examine testosterone levels in patients with bipolar disorder compared with healthy controls. METHOD: We examined baseline total testosterone levels and current depression scores in male and female patients with bipolar disorder and mild to moderate depression and healthy controls. RESULTS: A significant interaction between diagnosis and gender was observed (F(2,97)=9.791, P=0.002). Testosterone levels were significantly lower for male patients with bipolar disorder compared with male controls (P=0.001). Women with bipolar disorder had significantly higher testosterone levels than female controls (P=0.03). CONCLUSIONS: Disturbances in testosterone levels may represent an important neurobiological abnormality in bipolar disorder and may differ by gender. If these findings are confirmed, the use of gender appropriate treatment strategies for the normalisation of testosterone levels in bipolar disorder depression should be further explored. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

The impact of childhood adversity on suicidality and clinical course in treatment-resistant depression.

BACKGROUND: Childhood adversity is a risk factor for the development of depression and can also affect clinical course. We investigated this specifically in treatment-resistant depression (TRD). METHODS: One hundred and thirty-seven patients with TRD previously admitted to an inpatient affective disorders unit were included. Clinical, demographic and childhood adversity (physical, sexual, emotional abuse; bullying victimization, traumatic events) data were obtained during admission. Associations between childhood adversity, depressive symptoms and clinical course were investigated. RESULTS: Most patients had experienced childhood adversity (62%), with traumatic events (35%) and bullying victimization (29%) most commonly reported. Childhood adversity was associated with poorer clinical course, including earlier age of onset, episode persistence and recurrence. Logistic regression analyses revealed childhood adversity predicted lifetime suicide attempts (OR 2.79; 95% CI 1.14, 6.84) and childhood physical abuse predicted lifetime psychosis (OR 3.42; 95% CI 1.00, 11.70). LIMITATIONS: The cross-sectional design and retrospective measurement of childhood adversity are limitations of the study. CONCLUSIONS: Childhood adversity was common amongst these TRD patients and was associated with poor clinical course, psychosis and suicide attempts. Routine assessment of early adversity may help identify at risk individuals and inform clinical intervention.

Long-term symptomatic and functional outcome following an intensive inpatient multidisciplinary intervention for treatment-resistant affective disorders.

BACKGROUND: The natural history of treatment-resistant depression (TRD) is poor, with high rates of chronicity and recurrence. We describe longer-term symptomatic and functional outcome following multimodal intensive inpatient treatment for TRD. METHODS: Symptomatic and functional outcomes were assessed in 71 participants (unipolar, n=51; bipolar, n=20) with severe TRD previously treated at a specialist inpatient unit a median of 34 months (IQR 19-52) post discharge. We looked at outcomes in defined subgroups (unipolar, bipolar and psychotic) and at symptom clusters to see whether certain aspects of depression were more resistant to treatment than others. RESULTS: Symptomatic improvement during the admission was maintained at follow up: HDRS21 scores fell from admission (median 22; IQR 19-25) to discharge (median 12; IQR 7-16) and follow-up (median 10; IQR 4-18). Overall, two-thirds of patients were judged to have a good long-term outcome, while half remained in full remission at follow-up. Outcomes were more favourable in bipolar patients, patients without a history of psychosis and patients who were discharged in remission, although a minority of responders at discharge no longer met response criteria at follow up, and conversely some patients discharged as non-responders did subsequently respond. Non-remitting depression was characterised by three main factors; anxiety, cognitive difficulties and sleep disturbance. Those who remitted had better functional outcomes as did those who had experienced a more sustained response to treatment whilst inpatients. Quality of life was poor for those who did not respond to the treatment package. LIMITATIONS: Variable follow-up length. CONCLUSIONS: This difficult-to-treat population gained long-term benefits from multidisciplinary inpatient treatment. Treatment to remission was associated with more favourable outcomes. Non-responsive depression was characterised by specific symptom clusters that might be amenable to more targeted treatments.

Decreased resting-state interhemispheric coordination in first-episode, drug-naive paranoid schizophrenia.

BACKGROUND: Dysconnectivity hypothesis posits that schizophrenia relates to abnormalities in neuronal connectivity. However, little is known about the alterations of the interhemispheric resting-state functional connectivity (FC) in patients with paranoid schizophrenia. In the present study, we used a newly developed voxel-mirrored homotopic connectivity (VMHC) method to investigate the interhemispheric FC of the whole brain in patients with paranoid schizophrenia at rest. METHODS: Forty-nine first-episode, drug-naive patients with paranoid schizophrenia and 50 age-, gender-, and education-matched healthy subjects underwent a resting-state functional magnetic resonance imaging (fMRI) scans. An automated VMHC approach was used to analyze the data. RESULTS: Patients exhibited lower VMHC than healthy subjects in the precuneus (PCu), the precentral gyrus, the superior temporal gyrus (STG), the middle occipital gyrus (MOG), and the fusiform gyrus/cerebellum lobule VI. No region showed greater VMHC in the patient group than in the control group. Significantly negative correlation was observed between VMHC in the precentral gyrus and the PANSS positive/total scores, and between VMHC in the STG and the PANSS positive/negative/total scores. CONCLUSIONS: Our results suggest that interhemispheric resting-state FC of VMHC is reduced in paranoid schizophrenia with clinical implications for psychiatric symptomatology thus further contribute to the dysconnectivity hypothesis of schizophrenia.

Longitudinal course of symptom severity and fluctuation in patients with treatment-resistant unipolar and bipolar depression.

Little is currently known about the long-term course of symptom severity and fluctuation in patients with treatment-resistant depression (TRD). We assessed this using the longitudinal interval follow-up evaluation in 115 patients with TRD (84 unipolar, 31 bipolar) with 1-7 years (median 36 months) of follow-up. Of the follow-up months, 39.2% were spent asymptomatic and 21.1% at sub-threshold symptom level, while 15.8% were spent at mild, 13.9% at moderate, and 10.0% at severe depressive episode level. Significantly more unipolar than bipolar patients were continuously symptomatic during follow-up (43% vs. 29%). Patients had a mean of 1.0 (S.D.=1.2) symptom severity level fluctuations per year. High fluctuating patients had significantly poorer global functioning and quality of life. Although most patients with TRD achieve an asymptomatic state, they continue to fluctuate and experience depressive symptoms in the majority of months, mostly at subclinical or mild severity. However, there are important differences between unipolar and bipolar TRD, with unipolar patients more likely to experience an unremitting depressive state. Additionally, a more fluctuating longitudinal illness course is associated with poorer function and quality of life, and with a bipolar diagnosis. We suggest that the longitudinal illness course is an important outcome to be considered in future TRD research.

Reversal alterations of amplitude of low-frequency fluctuations in early and late onset, first-episode, drug-naive depression.

BACKGROUND: It is unclear how patients with early onset depression (EOD) and late onset depression (LOD) differ at the neural level. Using amplitude of low-frequency fluctuations (ALFF) approach, we are to test the hypothesis of the different abnormal neural activities between patients with EOD and LOD. METHODS: Fifteen patients with EOD, 15 patients with LOD, 15 young healthy subjects (HS) and 15 old HS were enrolled in the study. ALFF approach was employed to analyze the images. RESULTS: ANOVA analysis revealed widespread differences in ALFF values among the four groups throughout frontal, parietal, temporal, occipital cortex, cerebellum and limbic regions. Compared to LOD group, EOD group had higher ALFF in bilateral precuneus, superior medial frontal gyrus and superior frontal gyrus, and lower ALFF in left brainstem and left superior temporal gyrus. Compared to young HS, lower ALFF in left superior/inferior temporal gyrus, left lingual gyrus and right middle occipital gyrus and higher ALFF in left medial frontal gyrus and bilateral superior frontal gyrus were seen in the EOD group; in contrast, in the LOD group, lower ALFF in bilateral superior frontal gyrus and higher ALFF in left superior temporal gyrus were observed. Further ROC analysis suggested that the mean ALFF values in the bilateral superior frontal gyrus and left superior temporal gyrus could serve as markers to separate patients with EOD from individuals with LOD. CONCLUSIONS: Patients with EOD and LOD exhibit reversal pattern of abnormal ALFF in bilateral superior frontal gyrus and left superior temporal gyrus.

Abnormal amplitude low-frequency oscillations in medication-naive, first-episode patients with major depressive disorder: a resting-state fMRI study.

BACKGROUND: Recent resting-state fMRI studies on major depressive disorder (MDD) have found altered temporal correlation between low-frequency oscillations (LFOs). However, changes on the amplitudes of these LFOs remain largely unknown. METHODS: Twenty-two medication-naive, first-episode patients with MDD and 19 age-, sex-, education-matched healthy controls were recruited. Resting-state fMRI was obtained by using an echo-planar imaging sequence and the fractional amplitude of low-frequency fluctuations (fALFF) was calculated to investigate the amplitude of LFOs in the resting state. RESULTS: Compared with control subjects, patients with MDD showed significantly decreased fALFF in right cerebellum posterior lobe, left parahippocampal gyrus and right middle frontal gyrus and increased fALFF in left superior occipital gyrus/cuneus (p<0.05, corrected for multiple comparisons). Further receiver operating characteristic curves (ROC) analyses suggested that the alterations of fALFF in these regions might be used as markers to classify patients with MDD from healthy controls. CONCLUSIONS: These findings indicated LFOs abnormalities in MDD and the fALFF analysis might be a potential approach in further exploration of this disorder.

Early and late onset, first-episode, treatment-naive depression: same clinical symptoms, different regional neural activities.

BACKGROUND: Patients with early onset depression (EOD) and late onset depression (LOD) have distinctive risk factors and clinical pictures. Using regional homogeneity (ReHo) approach, we were to test the hypothesis of the different abnormal neural activity between patients with EOD or LOD. METHODS: Fifteen patients with EOD, 15 patients with LOD, 15 young healthy subjects (HS) and 15 old HS participated in the study. ReHo approach was employed to analyze the scans. RESULTS: ANOVA analysis revealed widespread differences in ReHo values among the four groups throughout frontal, parietal, temporal, occipital cortex, cerebellum and limbic regions. Compared to LOD group, EOD group had higher ReHo in right precuneus (PCu) and bilateral superior frontal gyrus, and lower ReHo in left superior temporal gyrus. Compared to young HS, lower ReHo in left parahippocampal gyrus and higher ReHo in left fusiform gyrus and bilateral superior frontal gyrus were seen in EOD group; in contrast, in LOD group, lower ReHo in right PCu and higher ReHo in left superior temporal gyrus and left Crus I of the cerebellum were observed. Further ROC analysis suggested that the mean ReHo values in right PCu and bilateral superior frontal gyrus could serve as markers to identify patients with EOD from individuals with LOD. LIMITATION: The large age gap may limit the translational value of our findings. CONCLUSIONS: Patients with EOD and those with LOD have abnormal neural activities in different brain regions, although the two groups share the same symptoms.

Abnormal regional spontaneous neural activity in first-episode, treatment-naive patients with late-life depression: a resting-state fMRI study.

BACKGROUND: The previous resting perfusion or task-based studies have provided evidence of functional changes in the brains of patients with late-life depression (LLD). Little is known, so far, about the changes in the spontaneous brain activity in LLD during the resting state. The aim of this study was to investigate the spontaneous neural activity in first-episode, treatment-naive patients with LLD by using resting-state functional magnetic resonance imaging (fMRI). METHODS: A novel analytical method, coherence-based regional homogeneity (Cohe-ReHo), was used to assess regional spontaneous neural activity during the resting state in 15 first-episode, treatment-naive patients with LLD and 15 age- and gender-matched healthy controls. RESULTS: Compared to the healthy controls, the LLD group showed significantly decreased Cohe-ReHo in left caudate nucleus, right anterior cingulate gyrus, left dorsolateral prefrontal cortex, right angular gyrus, bilateral medial prefrontal cortex, and right precuneus, while significantly increased Cohe-ReHo in left cerebellum posterior lobe, left superior temporal gyrus, bilateral supplementary motor area, and right postcentral gyrus (p<0.005, corrected for multiple comparisons). CONCLUSIONS: These findings indicated abnormal spontaneous neural activity was distributed extensively in first-episode, treatment-naive patients with LLD during the resting state. Our results might supply a novel way to look into the underlying pathophysiology mechanisms of patients with LLD.

Alterations of the amplitude of low-frequency fluctuations in treatment-resistant and treatment-response depression: a resting-state fMRI study.

BACKGROUND: Patients with treatment-resistant depression (TRD) and those with treatment-response depression (TSD) respond to antidepressants differently and previous studies have commonly reported different brain networks in resistant and nonresistant patients. Using the amplitude of low-frequency fluctuations (ALFF) approach, we explored ALFF values of the brain regions in TRD and TSD patients at resting state to test the hypothesis of the different brain networks in TRD and TSD patients. METHODS: Eighteen TRD patients, 17 TSD patients and 17 gender-, age-, and education-matched healthy subjects participated in the resting-state fMRI scans. RESULTS: There are widespread differences in ALFF values among TRD patients, TSD patients and healthy subjects throughout the cerebellum, the visual recognition circuit (middle temporal gyrus, middle/inferior occipital gyrus and fusiform), the hate circuit (putamen), the default circuit (ACC and medial frontal gyrus) and the risk/action circuit (inferior frontal gyrus). The differences in brain circuits between the TRD and TSD patients are mainly in the cerebellum, the visual recognition circuit and the default circuit. CONCLUSIONS: The affected brain circuits of TRD patients might be partly different from those of TSD patients.

Prospective evaluation of specialist inpatient treatment for refractory affective disorders.

BACKGROUND: Little data exist to inform the treatment of severe and resistant affective disorders. We report here the effectiveness of specialist multimodal inpatient treatment for refractory affective disorders. METHODS: Prospective evaluation of 225 consecutive patients admitted to the National Affective Disorders Unit between 2001 and 2008. RESULTS: Patients were highly treatment-resistant: most had already received ECT, lithium augmentation and over 10 prior treatment trials. Even so, sequential assessment with the Hamilton Depression Rating Scale found that 69% showed a clinical response (≥ 50% reduction in Hamilton score) to intensive therapy during admission; 50% continued to sustain a full response and 71% at least a partial response on discharge. Patients' self-ratings (57% very much or much improved, 24% slightly improved) and relative and referrer reports (75% and 68% respectively rated patients as improved) gave similar levels of improvement. LIMITATIONS: This was an observational study, without any untreated control group. The generalisability of the findings is limited by the highly specialised nature of the unit. CONCLUSIONS: Most patients with depression highly resistant to prior treatment respond to specialist and intensive multimodal inpatient therapy.

The Maudsley Staging Method for treatment-resistant depression: prediction of longer-term outcome and persistence of symptoms.

OBJECTIVE: A recently proposed multidimensional method of staging treatment resistance in depression, the Maudsley Staging Method (MSM), has been shown to predict short-term outcome of treatment. This study tested whether the MSM predicts longer-term clinical outcome. We hypothesized that patients with higher scores on the MSM would experience a worse longer-term outcome in terms of time spent in a depressive episode and level of functional impairment. METHOD: From May through July of 2008, we followed up patients with treatment-resistant depression discharged from an inpatient unit of an affective disorders service; all had MSM scores previously calculated from preadmission clinical data. We used the Longitudinal Interval Follow-up Evaluation (LIFE) chart to determine the monthly symptomatic course of depression blind to initial MSM scores. We employed a regression model to adjust for various confounding factors, including variable duration of follow-up, to determine the independent association of MSM scores with persistence of depressive disorder. RESULTS: We assessed 62 of 80 eligible patients (78%) in a median follow-up duration (interquartile range) of 29.5 (19.0-52.5) months. The MSM independently predicted (1) being in an episode for 50% or longer of the follow-up duration (OR = 2.11, 95% CI = 1.25 to 3.57), (2) being in an episode at the time of follow-up assessment (OR = 1.89, 95% CI = 1.17 to 3.05), (3) being persistently in an episode throughout the follow-up period (OR = 2.01, 95% CI = 1.14 to 3.54), and (4) total months spent in a depressive episode (OR = 1.22, 95% CI = 1.06 to 1.40). The MSM also predicted functional impairment. Antidepressant count and the Thase and Rush model did not independently predict persistence of depression or functional impairment. CONCLUSION: The MSM appears to have reasonable predictive validity regarding the longer-term course of illness, particularly persistence of depressive episodes. The MSM may be a useful, and possibly an improved, alternative to existing models of staging of treatment-resistant depression.

What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies.

BACKGROUND: Treatment-resistant depression (TRD) is relatively common and accounts for a large proportion of the overall burden caused by depression. We conducted a systematic review of outcome studies of TRD in order to summarise findings on the longer term outcome of TRD and make recommendations. METHODS: Studies were identified through MEDLINE (1960--June Week 1 2008), EMBASE (1974--June Week 1 2008) and PsycINFO (1967--June Week 1 2008) searches. We included studies that followed adults with highly probable TRD for a minimum of 6 months. Statistical analyses were conducted on selected outcome variables whenever possible. Methodological heterogeneity of studies prohibited formal meta-analysis. RESULTS: We identified nine outcome studies with a total of 1279 participants and follow-up duration of between 1 and 10 years. In the short term, TRD was highly recurrent with as many as 80% of those requiring multiple treatments relapsing within a year of achieving remission. For those with a more protracted illness, the probability of recovery within 10 years was about 40%. TRD was also associated with poorer quality of life and increased mortality. LIMITATIONS: Included primary studies were heterogeneous. CONCLUSIONS: TRD is associated with poorer clinical outcome, particularly among those who require multiple antidepressant medications. The main limitations of the review arise from the variability in recruitment procedures, definitions and outcome assessments of the original studies. We recommend further follow-up studies of carefully identified samples in order to gain a more detailed understanding of this domain of depression and plan effective interventions.